TolerGenics, Inc., an entrepreneurial biotechnology company established in 1997, is devoted to the development and commercialization of novel therapies for inducing and maintaining epitope-specific immune tolerance using B-cell delivery strategies. Based on the hypothesis that B-cell antigen presentation of self immunoglobulins would be highly tolerogenic, we are utilizing a patented technology (#5,817,308 "Tolerogenic fusion proteins of immunoglobulins and methods for inducing and maintaining tolerance") in which we engineer retroviral constructs containing multiple epitopes in frame at the N-terminus of a murine IgG1 heavy (H) chain. Recipients of peripheral B cells transfected with these vectors have been shown to be tolerant to the expressed genes. Data in three induced or spontaneous autoimmune models (uveitis with IRBP, EAE with MBP, diabetes in NOD mice) validate this paradigm in that significant clinical efficacy has been achieved. TolerGenics has chosen uveitis as its first clinical target because of the number of patients affected (estimated at 1-2 million Americans affected, with 45,000 new cases per year), and because of the clear endpoints for therapeutic efficacy (visual acuity). Because lymphocytes from patients with uveoretinitis have been shown respond to S-antigen (S-Ag), in this proposal, we wish to prepare constructs with human S-Ag linked to IgG H chains to extend this model to S-Ag-induced uveitis in both rats and HLA-transgenic mice. As a step toward future Phase I clinical trials, S-Ag will be linked in frame to human IgG4 H chain (as well as into our current murine IgG1 cassette) in order to test efficacy in both rats and mice challenged with Sag in adjuvant to induce experimental uveitis (EAU). Importantly, we will examine whether B-cell delivered gene therapy with S-Ag-Ig can ameliorate ongoing EAU and/or prevent the transfer of EAU with primed T cells, an important step to prove efficacy in an immune host. These will be important milestones for our therapeutic approach in cases of human uveoretinitis. The accomplishment of these aims will enable us to produce a specific product, an S-Ag-linked Ig vector, that can be used therapeutically to modulate autoimmunity in our first clinical trial of uveoretinitis. We predict that tolerance to a variety of target antigens in autoimmunity can be achieved via this technique since autologous B cells present the relevant epitopes in a haplotype-specific manner. This should also have application for tolerance therapeutic proteins in gene therapy.